There is considerable evidence that smooth muscle proliferation in atherosclerosis is controlled by factors released from platelets at sites of endothelial damage. Much less is known about the etiology of proliferation in hypertensive vascular disease. Endothelium, smooth muscle, and cardiac muscle all respond to as yet undefined stimuli by entering the cell cycle early in the course of hypertension. The increase in DNA or cell number persists in chronic hypertension and increased smooth muscle cell mass appears to play a critical role in the elevated peripheral resistance characteristic of hypertension. In our initial application we proposed that endothelial injury also lay as the basis of proliferation in hypertension. Most importantly, we suggested that cell proliferation itself might be causal in maintaining elevated blood pressure. We have made considerable progress in the development of methods to pursue this hypothesis during the two years of this grant. This progress has included our discovery that smooth muscle cells undergo two apparently different forms of replication: cell division in atherosclerosis and endoreplication in hypertension. The objective of our renewal application is a continued effort to explore the mechanisms of cell replication in the pathogenesis of hypertension with a continued interest in the role of platelets and an extension of that inquiry into the possibility that the different types of proliferative response seen following different stimuli reflect different states of smooth muscle differentiation.